Aryl substituted cyclohexenecarbinols

ABSTRACT

Compounds of the formula:   WHEREIN R is carboxy, lower carbalkoxy, methylol, carboxamide or carboxylic alkali metal salts, R&#39;&#39; is lower alkyl and Ar is substituted aryl are active agents for the suppression of animal reproduction.

'[22] Filed:

United States Patent [191 Karmas ARYL SUBSTITUTED CYCLOHEXENECARBINOLS [75] Inventor:

[73] Assignee: Ortho Pharmaceutical Corporation,

Raritan, NJ.

211 Appl. No.: 193,200

Related US. Application Data [63] Continuation-in-part of Ser. No. 747,075, July 24, 1968, abandoned, which is a continuation-in-part of Ser. No. 662,311, Aug 22, 1967, abandoned.

George Karmas, Bound Brook, NJ.

[56] References Cited UNITED STATES PATENTS 2,582,253 1/1952 Hogg et al. 260/520 1 Jan. 21, 1975 3,344,147 9/1967 Mcbane 2611/3265 OTHER PUBLICATIONS Nathan et al., Jour. Amer. Chem. Soc., Vol. 78 (1956) 6163-6166.

Primary Examiner-Bernard Helfin Attorney, Agent, or FirmBenjamin F. Lambert [57] ABSTRACT Compounds of the formula:

wherein R is carboxy, lower carbalkoxy, methylol, carboxamide or carboxylic alkali metal salts, R is lower alkyl and Ar is substituted aryl are active agents for the suppression of animal reproduction 5 Claims, No Drawings ARYL SUBSTITUTED CYCLOHEXENECARBINOLS This application is a continuation-in-part of copending application Ser. No. 747,075 filed July 24, 1968, which is in turn a continuation-in-part of US. Pat. application Ser. No. 662,311 filed Aug. 22, 1967 and both now abandoned.

The compounds of the present invention are of the formula:

Ar R and Ar wherein R is carboxy, lower carbalkoxy, methylol, carboxamide or carboxylic alkali metal salts, R is lower alkyl of up to 6 carbon atoms and Ar is 3,4- methylenedioxyphenyl, a-naphthyl, B-naphthyl or wherein R is hydrogen, hydroxy, lower alkoxy of up to 4 carbon atoms, lower acyloxy of up to 5 carbon atoms, or tetrahydropyranyl-2-oxy, R is hydrogen, hydroxy, lower alkyl of up to 4 carbon atoms, lower alkoxy of up to 4 carbon atoms, lower acyloxy of up to 5 carbon atoms, tetrahydropyranyl-Z-oxy, chlorine or trifluoromethyl, and R is hydrogen, hydroxy, lower alkyl of up to 4 carbon atoms, lower acyloxy of up to 5 carbon atoms, diethylaminoethoxy, thiomethyl, trifluoromethyl, dimethylamino, or tetrahydropyranyl-Z-oxy, and wherein at least one and not more than two of R R and R is hydrogen.

The compounds of the present invention which are preferred are [2-methyl-3-ethyl-4-(p-hydroxyphenyl)- 3-cyclohexenyl-lImethanol, [2-methyl-3-ethyl-4-(phydroxyphenyl-4-cyclohexenyl-l ]methanol, [4-(panisyl)-3-ethyl-2-methyl-3-cyclohexenyl-l ]methanol and [4-( p-anisyl )-3-ethyl-2-methyl-4-cyclohexenyll]methanol. They possess improved estrogenicity and anti-littering properties.

The following reaction scheme illustrates the prepa ration of precursor compounds of the present invention:

In the above illustrated reaction scheme, an aryl Grignard reagent is used. Any highly active arylmetallic reagent such as aryllithium, arylsodium or arylpotassium reagents may be used equally well to prepare the lactone (I). The acid used in the dehydration of the hydroxy acid (II) is an acid of the type which produces a carbonium ion from the tertiary alcohol portion of the hydroxy acid and may be any strong organic or inorganic acid. While almost any Lewis acid may be used, p-toluenesulfonic acid, sulfuric acid, phosphoric acid, perchloric acid, iodine, boron trifluoride, perhalocarboxylic acids, and halides of boron, aluminum, tin and antimony are particularly useful. The solvent in which the dehydration is performed is generally acetic acid, but other organic solvents, such as hydrocarbons, ethers, esters, ketones, alcohols, etc., may be used. The dehydration of the hydroxy acid may lead to the production of certain dehydrated acid isomers in addition to those of Formula III a. and [II b. Chemical purification as well as chromatography and recrystallization are therefore useful in isolating the desired products.

Generally, the A -isomer (Formula III a.) is the predominant product. Prolonged heating of the dehydration mixture will cause isomerization of A to the A isomer and recrystallization affords the 3- cyclohexenecarboxylic acid.

The hydroxy acids of Formula ll may also be prepared by the reaction of an aryl Grignard reagent with a 2-lower alkyl-3-lower alkyl-4-ketocyclohexanecarboxylic acid.

The hydroxyacids of Formula [I may be converted to the corresponding hydroxyesters, which upon dehydration yield the unsaturated esters. The unsaturated esters, upon saponification, yield a mixture of the isomers of Formulae III a. and Ill b. The dehydration may be accomplished with any of the strong acids mentioned above, as well as with phosphorus halides and sulfur halides in the presence of such bases as pyridines, quinolines, trialkylamines, dialkylanilines, etc., in any solvent which is not reactive with the halides. The saponifi- ArMgBr O COOC H OH j Ar COOH ATM Strong Acid R' R cation is performed with an alkali or alkaline earth hydroxide or carbonate in the presence of an alkali-stable solvent.

The dehydrated acids of Formulae III a. and Ill b. may also be prepared by a Diels-Alder type of synthesis, as follows:

I. R R

COOH AI COOEI R R R III-8.. III.b.

Ar-C 2 CH2=CHCOOH CH==CH ArrC: 2

The o-acetoxyphenyl-hydroxy acids of Formula 11 undergo spontaneous decomposition at room temperature as follows:

As exemplified hereinafter, the esters, amides and methylols may be prepared by methods generally known in the art.

The following examples illustrate the preparation of the compounds of the invention:

' REACTION OF HYDROXYACIDS WITH BORON TRIFLUORIDE EXAMPLE I 2-Methyl-3-ethyl-4-(p-thioanisyl)-4- cyclohexenecarboxylic acid A suspension of 4.0 g. of 2-methyl-3-ethyl-4- 40 hydroxy-4-(p-thioanisyl) cyclohexanecarboxylic acid in 75 ml. of ether is stirred and 6 ml. of boron trifluoride etherate is added. The mixture is stirred at 25C. for 5 hours. Ice is added and the ether solution is extracted three times with 7% aqueous potassium carbonate to separate the acids from the neutral products. The combined carbonate extract is acidified with dilute hydrochloric acid and extracted with ether. The ether extract is dried over anhydrous sodium sulfate and evaporated to give a residue. The residue is recrystallized from ether to afford 2-methyl-3-ethyl-4-(p-thioanisyl)- 4-cyclohexenecarboxylic acid, m.p. l49-150C.

Calcd. for C, H O S: C, 70.37; H, 7.63 Found: C, 70.39; H, 7.70

Ahmax: 5.90, 7.78, 9.11, 11.71, 12.15, 12.48,

13.80p.(KBr.) NMR(CDC1;,): shows vinyl H at 5.62 p.p.m.

EXAMPLE ll 2-Methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4- cyclohexenecarboxylic acid Following the procedure of Example I, but starting with 2-methy1-3-ethyl-4-hydroxy-4-(o-methoxy-phydroxyphenyl)cyclohexanecarboxylic acid and carry- ,5

iv a ArQcOOH R R I A I COOH Found: c, 70.13; a, 7.46

Mtmax: 5.90, 8.35, 8.62, 9.65, 10.45, 12.00, 12.11, 12.50u. (KBr) coon NMR (pyr.): shows alkyl pattern of A.

EXAMPLE lIl 2-Methyl-3-ethyl-4-(o,p-dihydroxyphenyl)-4- cyclohexenecarboxylic acid Following the procedure of Example 1, but starting with 2-methyl-3-ethy1-4-hydroxy-4-(o,pdihydroxyphenyl) cyclohexanecarboxylic acid and carrying out the reaction for 10 minutes, there is afforded upon recrystallization from methylene chloride and carbon tetrachloride, 2-methyl-3-ethyl-4-(o,pdihydroxyphenyl)-4-cyclohexenecarboxylic acid, m.p. 85C. Mmax: 2.90-3.10, 5.87, 7.37, 8.60, 8.99, 11.75-1 1.90p.. (KBr.) NMR (CDC1 +CD CO D): shows vinyl H at 5.69 p.p.m.

REACTlON OF HYDROXY AClDS WITH AN ACID CATALYST EXAMPLE iv 2-Methyl-3-ethyl-4-(m-hydroxyphenyl)-4- cyclohexenecarboxylic acid To a gently boiling solution of 1.5 g. of 2-methyl-3-- ethyl-4-hydroxy-4-(m-hydroxyphenyl) cyclohexanecarboxylic acid in 50 ml. of acetic acid is added 0.15 g. of p-toluenesulfonic acid monohydrate. This mixture is refluxed for 5 minutes and then to it is added 0.15 g. of sodium acetate. After evaporation of the acetic acid solution, a pasty residue is obtained. The residue is shaken with ether and water and the layers are then separated. The ether layer is extracted three times with 7% aqueous potassium carbonate to separate acidic from neutral products. The combined carbonate extract is acidified with dilute hydrochloric acid and is extracted with ether. The ether solution is dried over anhydrous magnesium sulfate and is evaporated to dryness. The residue is recrystallized from acetone to afford 2-methyl-3-ethyl-4-(m-hydroxyphenyl)-4- cyclohexenecarboxylic acid, m.p. -168C.

Calcd. for C ,,H O C, 73.82; H, 7.74 Found: C, 72.74; H, 7.85 Mtmax: 3.02, 5.88, 7.80, 8.02, 11.50, 11.95, 12.72, 13.73 14.21 1. (KBr.) NMR (pyr.): shows alkyl pattern of A. 5

EXAMPLE V 2-Methyl-3-ethyl-4-(3,4-methylenedioxyphenyl)-4- cyclohexenecarboxylic acid Following the procedure of Example 1V, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(3,4- methylenedioxyphenyl)-cyclohexanecarboxylic acid, there is afforded 2-methyl-3-ethyl-4-(3,4- methylenedioxyphenyl)-4-cyclohexenecarboxylic acid, m.p. 173174C.

CalCd. for C17H2404I C, H, Found: C, 70.59; H, 6.93 Mtmax: 5.91, 8.06, 9.57, 10.58, 12.22, 13.89, 14.50 a. (KBr.) NMR (CDCl shows vinyl H at 5.59 p.p.m. 20

EXAMPLE VI methyl-3-ethyl-4-(m-tolyl)-3-cyclohexenecarboxylic acid, m.p. l00-102C.

Calcd. for C, H,,O C, 79.03; H, 8.58

Found: C, 79.29; H, 8.41 Mtmax: 5.89, 7.99,11.30,12.72,13.41,14.1lp..(KBr) NMR (CDCl;,): shows no vinyl H.

EXAMPLE VII 2-Methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-4- cyclohexenecarboxylic acid p-toluenesulfonate Following the procedure of Example IV but starting with 2-methyl-3-ethyl-4-hydroxy-4-(pdiethylaminoethoxyphenyl)-cyclohexanecarboxylic acid and using 1.0 g. of p-toluenesulfonic acid and no sodium acetate, the residue from low-temperature evaporation of the acetic acid solution is recrystallized from acetone to afford 2-methyl-3-ethyl-4-(pdiethylaminoethoxyphenyl)-4-cyclohexenecarboxylic acid p-toluenesulfonate, m.p. 150-160C.

Mtmax: 5.80, 8.08, 8.50, 8.64, 8.88, 9.62, 9.87, 12.00, 12.27 a. (KBr.) NMR (CD CO D): shows vinyl H at 5.59 p.p.m.

In some cases, the product formed contains A and N-isomers which cannot be separated by fractional crystallization. Chromatography is used to effect the separation. The crude acid mixture is developed 'on a silicic acid column, which is then eluted with gradually increasing amounts (0.1-2.0%) of ethyl acetate in benzene. The A -isomer is the first eluted acid, and eluate residues with similar infrared spectra are combined and recrystallized several times from ether or nitromethane to afford the 4-cyclohexenecarboxylic acid. Middle fractions from the chromatograph are a mixture of A -and A -acids and can only be rechromatographed. The late fractions are rich in A -isomers and are combined and recrystallized from ether, acetone, hcxanc, nitromethane or methylene chloride to afford the 3- cyclohexenecarboxylic acid.

EXAMPLE VIII 2-Methyl-3-ethyl-4-(o-anisyl)-3-(and cyclohexenecarboxylic acid Following the procedure of Example IV, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(o-anisyl) cyclohexanecarboxylic acid, there is afforded, after purification by chromatography, as shown in Example VII, 2-methyl-3-ethyl-4-(o-anisyl)-4-cyclohexenecarboxylic acid, m.p. 148-149C.

Calcd. for C H O C, 74.42: H, 8.09

Found: C, 74.47; H, 8.27 Mmax: 5.87, 8.02, 9.68, 11.67, 13.22, 13.52, 13.90 1. (KBr.) NMR (CDCI shows vinyl H at 5.58 p.p.m., and 2- methyl-3-ethyl-4-(o-anisyl)-3-cyclohexenecarboxylic acid, m.p. 160162C.

Calcd. for C H O C, 74.42; H, 8.09

Found: C, 74.53; H, 8.34 Mmax: 5.88, 8.02, 8.12, l3.17u(KBr.) NMR (CDCI shows no vinyl H.

EXAMPLE IX 2-Methyl-3-ethyl-4-(p-tolyl)-3-(and 4)cyclohexenecarboxylic acid Following the procedure of Example 1V, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(p-tolyl)cyclohexanecarboxylic acid, there is afforded, after purification by chromatography, as shown in Example V11. 2- methyl-3-ethyl-4-(p-tolyl)-4-cyclohexenecarboxylic acid, m.p. 173-175C.

Calcd. for C H O C, 79.03; H, 8.58

Found: C, 78.96; H, 8.63 Mmax: 5.90, 8.07, 11.78, 12.16, 12.41, 13.20, 13:84p.(KBr.) NMR (CDCl shows vinyl H at 5.61 p.p.m., and 2- methyl-3-ethyl-4-(p-tolyl)-3-cyclohexenecarboxylic acid, m.p. 187-188C.

Calcd. for C H O C, 79.03; H, 8.58

Found: C, 78.59; H, 8.74 Mmax: 5.89, 7.99, 11.47, 12.23, 13.38, 14.59;: (KBr.) NMR (CDCI shows no vinyl H.

EXAMPLE X 2-Methy1-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3- cyclohexenecarboxylic acid p-toluenesulfonate A mixture of 3.5 g. of 2-methyl-3-ethyl-4-hydroxy-4- (p-diethylaminoethoxyphenyl)cyclohexanecarhoxylic acid and 2.7 g. of p-toluenesulfonic acid monohydrate in ml. of acetic acid is refluxed for 5 hours and is then evaporated to remove acetic acid. The pasty residue is recrystallized twice from acetone to afford 2- methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3- cyclohexanecarboxylic acid p-toluenesulfonate, m.p. 172173C.

Calcd. for C H O NS: C, 65.59; H, 7.77

Found: C, 65.45; H, 7.72 Mmax: 5.80, 8.108.20, 8.50-8.70, 8.88, 9.62, 9.87. 12.21, 13.57, 14.62 p (KBr) NMR (CD CO D): shows no vinyl H.

EXAMPLE XI 2-Methyl-3-ethyl-4-( p-diethylaminoethoxyphenyl)-3- cyclohexenecarboxylic acid 7 A mixture of 0.2 g. of 2-methyl-3-ethyl-4-(pdiethylaminoethoxyphenyl)-3-cyclohexenecarboxylic acid p-toluenesulfonate (as prepared according to Example X), 15 m1. of ether, 3 m1. of water, and 0.9 ml.

8 Found: C, 69.12; H, 6.70 ltltmaxz 5.90, 7.97,11.89,12.72,13.08,13.60,14.33p.. (KBr.) NMR (CDC1 shows vinyl H at 5.65 p.p.m., and 2- of a solution of 1.6 g. sodium hydroxide in 100 ml. of methyl-3-ethyl-4-(m-chlorophenyl)-3- water is stirred at 25C. for 20 minutes. The layers are cyclohexenecarboxylic ac -P' C. permitted to separate and the ether layer is removed, Calcd. for C H O Cl: C, 68.92; H, 6.87 dried over anhydrous magnesium sulfate and evapo- Found: C, 68.78; H, 6.70 rated to a viscous residue. The residue is recrystallized Mmax: 5.88, 8-0 14-30 1 -l from nitromethane to afford 0.1 g. of 2-methy1-3-ethyl- 10 NMR (CDCl;,): shows only a trace of vinyl H. 4-(p-diethylaminoethoxyphenyl)-3- Following the procedure of Example X11, but starting cyclohexenecarboxylic acid, m.p. 130138C. with the appropriate 4-hydroxy acid there are pre- Calcd. for C H O N: C, 73.50; H, 9.25 pared:

Analysis on 1. 1 1 y L Gum Mm. Ex. CyClOllGXQHCCHIbOXYllU1101(1 C. C 11 C (K1312) NMR X1\" 2-mctl1yl-3-etl1yl-4-(n1-l1ydroxyphcnyl)-A- 192-105 73.82 7. 74 73.62 7.86 3.01, 5.83, 8.07, 8.49, 11.77, 12.24, (lytz) shows alkyl 7 V 12.75, 14.17 1. pattern 01' A. )W 2-1n0t11y13-ethy1-4-(o-hydroxyphenyl)-A 140-143 73.82 7. 74 73.82 7. 80 5.87, 8.00, 8.17, 8510,1110, 11.40, (Cl).'1(:()2l)) shows 13.20, 1 1.42 1. nlkyl pnttorn 01A. X\I 2-Inetl1y13-et11y1-4-(o-mctlioxy-p-acetoxy- 158160 68. 65 7.28 68.07 7. 5.65, 5.88, 8.27, 8.00, 0.61, 0.81, (CD013) shows no p11eny1)-A 10.30, 11.11, 11.00 1. viny 11. XVII... 2-rnethyL30tl1yl-4-(o,p-diacetoxyplienyh- 180-182 66.65 6.71 (16.50 6.68 5.68, 5. 0, 8.30-8.40, 8.70, 11.81, (ED300110 shows A-. 11.13, 14.30 1. nlkyl pnttorn 01A. 20 111" 2-metliyl-3-ethyl4- (3, l-methyleuedioxy- 155-157 70. 81 6.110 70.07 7. 11 5.87, 8.00 0.57, 10.03, 12.21, (111)0111) shows no 7 plien )-A3-. 13.30, 14.46 1. vinyl 11. XIX. 2-1nethyl-3-ethyl-4-(u-napht11y1)-A 155457 81. 60 7. 53 81.87 7.55 5.0 0, 7.82, 8.00, 11.80, 12.50, (0 1 011) shows vinyl 2.83 v.7. XX. 2-1netl1yl-3-etl1y1-4-(B-naphthyD-A 162-164 81.60 7. 53 81.80 7.51 5.80, 7.8 ,11.01,12.10,13.48,1. (()l1[)?Jll )sh1 ul s 1nyl .1571 XXL... 2-n10t11yl-3-pr0pyl-4-(p-anisyl)-A 174-175 74. 07 8. 75.07 8.38 5.80, 8.04, 0.51, 11.01, 12.20, cobra 811302 1 1 0 14.18 1. vinyl 11.

Found: C, 73.72; H, 9.19 EXAMPLE XXll [L- 2 y y 4 y r I cyclohexenecarboxylic acid NMR (CD3CO2D)' Shows no vmyl A mixture of 6.0 g. of 2-methyl-3-ethyl-4-hydroxy-4- EXAMPLE XII (m-anisyl)cyclohexanecarboxylic acid and 0.9 g. of y y p y p-toluenesu lfomc acid monohydrate in 150 ml. of

acetic acid is refluxed for three hours and is then evapcyclohexenecarboxyhc acid or ted to a ast residue Th r sidu is hak ith A mixture of 3.5 g. of 2methyl-3-ethyl-4-hydroxy-4- a p y e e e s an W (p-thioanisyl)cyclohexanecarboxylic acid and 0.6 g. of p-toluenesulfonic acid monohydrate in 100 ml. of acetic acid is refluxed for a period of 5 hours and then to this is added 0.6 g. of sodium acetate and the mixture is evaporated to remove acetic acid. The pasty residue is shaken with ether and water and the ether phase is extracted three times with 7% aqueous potassium carbonate. The combined carbonate solution is acidified with dilute hydrochloric acid and extracted with ether. After drying over anhydrous magnesium carbonate and evaporation of the ether, the residue is recrystallized from methylene chloridehexane to afford 2-methyl-3- ethyl-4-(p-thioanisyl)-3-cyclohexenecarboxylic acid, double m.p. 145-147, then 151152C.

Calcd. for C, H O S: C, 70.37; H, 7.63

Found: C, 70.58; H, 7.71 Mmax: 5.88, 8.00, 9.11, 11.47, 12.18, 13.26, 14.50 1. (KBL) NMR (CDCl;,): shows no vinyl H.

EXAMPLE XlIl ether and water, the layers are separated and the ether phase is extracted three times with 7% aqueous potassium carbonate. The combined carbonate extract is acidified with dilute hydrochloric acid and is extracted with ether. The extract is chromatographed as in Example VII on a silicic acid column and the eluates afford, upon recrystallization from chloroform, 2-methy1-3- ethyl-4-(m-anisyl)-4-cyclohexenecarboxylic acid, m.p. l11C.

Calcd. for C H O C, 74.42; H, 8.09

Found: C, 74.61; H, 8.08 Mtmax: 5.86, 8.26, 8.49, 9.47, 11.13, 12.81, 13.22, 13.84 1. (KBr.) NMR (CDC1 shows vinyl H at 5.68 p.p.m. and 2- methyl-3-ethyl-4-(m-anisyl)-3-cyclohexenecarboxylic acid, m.p. l26127C.

Calcd. for C H O C, 74.42; H, 8.09

Found: C, 74.27; H, 8.09 NMR (CDC1 shows no vinyl H.

EXAMPLE XXIIl 2-Methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-4- cyclohexenecarboxylic acid To a solution of 1.0 g. of 2-methyl-3-ethyl-4-(o,pdihydroxyphenyl)-4-cyclohexenecarboxylic acid (as prepared according to Example 111) in 20 m1. of pyridine is added, with stirring, 2 ml. of acetic anhydride. The solution is maintained at 25C. for 4 hours and it is then hydrolyzed with ice and water and the mixture is acidified with hydrochloric acid and extracted with ether. The ether solution is washed with cold hydro- EXAMPLE XXIV 2-Methyl-3-ethyl-4-(o-hydroxy-p-acetoxyphenyl)-4- (and 3)-cyclohexenecarboxylic acid One gram of 2-methyl-3-ethyl-4-hydroxy-4-(o,pdiacetoxyphenyl)cyclohexanecarboxylic acid is held at 25C for 3 weeks. The decomposition products are fractionally crystallized from nitromethane to afford 0.2 g. of 2-methyl-3-ethyl-4-(o-hydroxy-pacetoxyphenyl)-4-cyclohexenecarboxylic acid, m.p. 151-155C.

Calcd. for C H O C, 67.91; H, 6.97

Found: C, 68.04; H, 6.93 )tkmaxz 2.91, 5.75, 5.87, 8.10, 8.75, 9.80,10.16,10.26, 1100,1178,13.81u.(l(Br.)

NMR (CDCl shows vinyl H at 5.72 p.p.m. and, from carbon tetrachloride, 0.3 of 2-methyl-3-ethyl-4-(ohydroxy-p-acetoxyphenyl)-3-cyclohexenecarboxylic acid, m.p. l37139C.

Calcd. for C H O C, 67.91; H, 6.97

Found: C, 67.87; H, 6.86 )tkmax: 2.90, 5.72, 5.86, 8.10, 8.73, 9.12, 9.79, 10.22, 10.98 11.58 1.. (KBr.)

NMR (CDCl shows no vinyl H.

The esters of the compounds of the present invention may be prepared by any one of a number of methods. For example, the carboxylic acid prepared in accordance with any of the preceding Examples may be converted to its alkali metal or alkaline earth metal salt, which in turn is reacted with an alkyl or aralkyl halide, sulfate, or sulfonate in an alkali-stable medium such as dimethylformamide, formamide, dimethylsulfoxide, hydrocarbons, ethers, etc. Likewise, an acyl halide prepared by the reaction of the appropriate carboxylic acid with a sulfur halide or a phosphorus halide may be reacted with an alcohol or phenol in an acid-resistant solvent such as hydrocarbons, ethers, esters, tertiary bases, chlorinated hydrocarbons, etc.; or an acid halide may be reacted with the metal (alkoxide) derivative of almost any alcohol or phenol in an acid-resistant solvent.

Other methods for preparing esters are:

1. the reaction of the appropriate carboxylic acid with diazoalkane in an inert solvent,

2. the reaction of the appropriate carboxylic acid with an alcohol in the presence of strong organic or inorganic acid catalysts, and by 3. ester interchange by heating one ester in a large excess of another ester in the presence of acidic or basic catalysts.

EXAMPLE XXV Butyl cyclohexenecarboxylate A solution of 0.6 g. of 2-methyl-3-ethyl-4-(p-tolyl)-3- cyclohexenecarboxylic acid in 5 ml. of 10% methanolic sodium hydroxide is diluted with 65 ml. of dimethylformamide. The solution is evaporated to a volume of 35 ml. and the resulting suspension is cooled to 10C., stirred and treated with 1.0 ml. of dibutyl sulfate. After 1 hour at 25C., this'mixture is evaporated and the residue is shaken with ether and water. The ether phase is washed with dilute alkali, dried and evaporated, and the residue is distilled to afford butyl 2-methyl3-ethyl- 4-(p-tolyl)-3-cyclohexenecarboxylic, an oil of b.p. 117C. at 0.005 mm.

Anal. Calcd. for C H O z C, 80.21; H, 9.62. Found: C, 80.14; H, 9.80. Mmax: 5.78, 8.61, 9.78, 12.28 p. NMR (CDC1 0.75, 0.87, 0.99, 1.06 ppm.

EXAMPLE XXVI Hexyl 2-Methyl-3-ethyl-4-(3,4- methylenedioxyphenyl)-3-cyclohexenecarboxylatc A mixture of 0.3 g. of 2-methyl-3-ethyl-4-(3,4- methylenedioxyphenyl)-3-cyclohexenecarboxylic acid and 3 ml. of thionyl chloride is refluxed for 15 minutes and then it is evaporated and the residue is distilled to afford 0.3 g of the acid chloride. a viscous orange oil of b.p. -140 at 0.02 mm. The distilled acid chloride is dissolved in 4 ml. of n-hexyl alcohol and to this is added 4 ml. of pyridine. The mixture is heated at 90 for 30 minutes and then five drops of water are added and the heating is continued for 5 minutes. The reaction mixture is diluted with ether and then it is washed with dilute acid, water, and dilute alkali. The final ether solution is dried and evaporated, and the residue is distilled to afford 0.3 g. of hexyl 2-methyl3-ethyl-4-(3,4- methylenedioxyphenyl)3-cyclohexenecarboxylate, an oil of b.p. -160 at 0.001 mm.

Anal. Calcd. for C23H3204: C, H,

Found: C 74.10; H, 8.75 Mmax: 5.78, 8.10, 8.60, 9.57, 10.62, 11.60, 1231p. NMR (CDCl;,): 0.76, 0.88, 0.92, 1.00, 1.03 ppm. Typical esters which are prepared are: Methyl 2-methyl-3-ethyl-4-(o-methoxy-phydroxyphenyl)-4-cyclohexenecarboxylate, Methyl 2-methyl-3-ethyl-4-(3,4- methylenedioxyphenyl)-4-cyclohexenecarboxylate,

methylenedioxyphenyl )-4-c'yclohexenecarboxylate, Octyl 2,3-dimethyl-4-(p-diethylaminoethoxyphenyl )-4- cyclohexenecarboxylate,

Octyl 2,3-dibutyl-4-(m-hydroxyphenyl )-3- cyclohexenecarboxylate, and

Octyl 2-ethyl-3-propyl-4-( a-naphthyl )-4- cyclohexenecarboxylate.

EXAMPLE XXVIl 2-Methyl-3-ethyl-4-(p-trifluoromethylphenyl)-3- cyclohexenecarboxylic acid A solution of 9.0 g. of p-toluenesulfonic acid monohydrate in 45 ml. of acetic anhydride is evaporated under vacuum to a syrupy residue of anhydrous sulfonic acid. The syrup is dissolved in 100 ml. of acetic acid and this solution is again evaporated to a syrupy residue to which is added 9.0 g. of methyl 2-methyl-3- 1 1 ethyl-4-hydroxy-4-(p-trifluoromethylphenyl)cyclohexanecarboxylate and 450 ml. of acetic acid. The mixture is stirred, rapidly heated, and boiled for 15 minutes. W This dehydration solution is cooled to 70C. and 7.0 g. of sodium acetate is added. The mixture is evaporated under vacuum to a pasty residue which is shaken with ether and water. The ether phase is washed twice with aqueous potassium bicarbonate, dried over anhydrous magnesium sulfate and evaporated to an oil which is a mixture of the A and A-isomers of methyl 2-methy1-3- ethyl-4-(p-trifluoromethylphenyl)cyclohexenecarboxylate.

The mixture of dehydrated esters is refluxed with stirring for two hours in 90 ml. of methanol and 90 ml. of water containing 9.0 g. of sodium hydroxide. The resulting clear solution is diluted with a large volume of water and is acidified with hydrochloric acid to precipitate the dehydrated acid. The precipitate is filtered off and dried in air. The dry precipitate is chromatographed on silicic acid, eluting with ethyl acetatebenzene. Eluates rich in the A -isomer are first obtained from the column, and these are followed by mixed A and A and then by the A -rich fractions. These changes are followed by infrared spectroscopy. The portions which are largely A -isomer are combined and recrystallized several times from 25% aqueous methanol to afford 1.3 g. of white prisms of 2-methyl-3- ethyl-4-(p-trifluoromethylphenyl)-3- cyclohexenecarboxylic acid, m.p. 174176C.

Calcd. for C17H1902F3: C, H,

Found: C, 64.83; H, 5.97 Mmax: 5.88, 7.53, 8.57, 8.85, 9.32, 11.72, 12.00, 1458 2. (KBr) kmax: 247 mu. (6 5820, methanol) EXAMPLE XXVIII 2-Methyl-3-ethyl-4-(p-trifluoromethylphenyl)-4- cyclohexenecarboxylic acid The residues from early chromatographic elutions, described in Example XXVII, are recrystallized several times from ether-hexane to afford 1.5 g. of 2-methyl-3- ethyl-4-(p-trifluoromethylphenyl)-4- cyclohexenecarboxylic acid, m.p. 181-183C.

Calcd. for C, H O F C, 65.40; H, 6.13

Found: C, 65.67; H, 6.26 Mmax: 5.90, 7.55, 8.53, 8.80, 9.34, 11.65, 11.95 p (KBr.)

)tmax: 244 mp. (9060, methanol) NMR (CDCl;,): shows vinyl H at 5.70 ppm.

The alkali metal salts of the hexenyl acids of the invention are prepared by mixing equivalent amounts of the appropriate hexenyl acid and an alkali metal carbonate, bicarbonate or hydroxide in a solvent such as water or methanol until the neutralization reaction is complete. The reaction mixture is then evaporated to dryness to afford the alkali metal salts of the acid.

Methylols may be prepared by the reduction ofa carboxylic acid, carboxylic ester or carbonyl halide with lithium aluminum hydride. The reductions may be performed in any inert solvent, but ethers are most favored because they dissolve lithium aluminum hydride.

EXAMPLE XXIX [2-Methy1-3-ethyl-4-(m-tolyl)-4-cyclohexeny1-1] methanol To a stirred solution of 0.15 g. of 2-methy1-3-ethyl- (m-tolyl)-4-cyclohexenecarboxy1ic acid in 10 ml. of tetrahydrofuran is added 0.4 g. oflithium aluminum hydride. The mixture is stirred at 25 for 20 hours and then it is poured into ice and water. The hydrolysis mixture is acidified with hydrochloric acid and filtered, the filter cake being washed thoroughly with ether. After separation of the filtrate layers, the ether solution is washed with dilute aqueous sodium hydroxide, dried, and evaporated to a residue which is distilled to afford 0.12 g. of [2-methyl-3-ethyl-4-(m-tolyl)-4- cyclohexenyl-1]methano1, a viscous oil, b.p. -110 at 0.001 mm.

Anal. Calcd. for C H O: C, 83.55; H, 9.90

Found: C, 83.30; H, 9.76 MMax: 3.00, 9.65, 9.91,11.80,12.53,12.81,14.14 u. NMR (CDCl;,): 0.70, 0.82, 0.94; 0.82, 0.93; 5.63 ppm.

Following the procedure of Example XXIX, the appropriate cyclohexenyl acid affords [2-Methyl-3-ethyl- 4-(3,4-methylenedioxyphenyl)-3-cyclohexenyl-1] methanol; viscous oil of b.p. -130 at 0.001 mm.

Anal. Calcd. for C H O C, 74.42; H, 8.08

Found: C, 74.11; H, 8.20 Mmax: 3.00, 8.03, 8.20, 9.59, 10.63, 11.58, 1231 1.. NMR (CDC1 0.73, 0.86, 0.99,; 0.89, 1.00 ppm.

Utilizing 2-methyl-3-ethyl-4-(p-anisyl)-4- cyclohexene carboxylic acid and following the procedure of Example XXIX, [2-methy1-3-cthyl-4-(panisyl)-4-cyclohexenyl-1] methanol is prepared as a colorless oil of b.p. 140C/0.03 mm which is recrystallized from pentane to yield white granules of m.p. 71-72C.

Anal. Calcd. for C, H O C, 78.42; H, 9.29

Found: C, 78.51; H, 9.30 Mmax: 3.00, 7.93, 8.48, 9.63, 11.90, l2.33;t(KBr) NMR (CDCL 0.69, 0.79, 0.87, 0.90, 0.97, 1.02

From the corresponding A acid, [2-mcthyl-3-cthyl- 4-(p-anisyl)-3-cyclohexenyl-1] methanol is similarly prepared as a colorless viscous oil of b.p. 129132C/.001 mm.

Anal. Found: C, 78.25 H, 9.29

Mmax: 2.99, 8.02, 8.47, 8.71, 9.62, 11.23,

12.03;.t(neat) NMR (CDCL 0.72, 0.84, 0.96, 0.89, 1.00

Again following generally the procedure of Example XXIX, and starting with 2-methyl-3-ethyl-4-(phydroxyphenyl)-4-cyclohexenecarboxylic acid, [2- methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl- 1] methanol is prepared as white prisms of m.p. 166-167C.

Anal. Calcd. fOr C16H2202I C, H,

Found: C, 78.01; H, 9.06 Mmax: 2.92, 6.61, 8.00, 8.17, 9.97, 11.76, 12.10;L. (KBr) From the corresponding A acid, [2-methy1-3-ethyl- 4-(p-hydroxyphenyl)-3-cyclohexenyl-1] methanol is similarly prepared as white prisms which melt at 102103 C.

Anal. Found: C, 77.33; H, 9.61 Mmax: 2.96, 3.10, 6.61, 8.02, 9.77, 9.83, 11.21, 12.0911. (KBr.)

In like manner there are prepared: [2-methy1-3-ethyl-4-(m-tolyl)-3-cyc1ohexeny1-1 methanol, [2-methy1-3-ethyl-4-(3,4-methy1enedioxyphenyl)-4- cyclohexenyl-1]-methanol, [2-methy1-3-ethy1-4-(o-methoxy-p-hydroxyphenyl)-4- cyclohexenyl-1]-methanol, [2-ethy1-3-propyl-4-(m-toly1)-3-cyclohexenyl-1] methanol,

[2-methy1-3-ethyl-4-(p-tolyl)-3-cyclohexenyl-1] methanol,

13 ethyl-4-hydroxy-4-(p-trifluoromethylphenyl)cyclohexanecarboxylate and 450 ml. of acetic acid. The mixture is stirred, rapidly heated, and boiled for 15 minutes. [2-methyl-3-ethyl-4-(p-tolyl)-4-cyclohexenyl-1] methanol, [2,3-dimethyl-4-(p-diethylaminoethoxyphenyl)-4- cyclohexenyl-1]-methanol, [2,3-dibutyl-4-(m-hydroxyphenyl)-3-cyclohexenyl-l] methanol, [2-ethyl-3-propyl-4-(a-naphthyl)-4-cyclohexenyl-1 methanol, [2-methyl-3-ethyl-4(o,p-dihydroxyphenyl)-4- cyclohexenyl-1] methanol, [2-methyl-3-ethyl-4-(m-anisyl)-4-cyclohexenyl-1] methanol, and [2'methyl-3-ethyl-4-(m-anisyl)-3-cyclohexenyl-1] methanol.

Amides may be prepared by reacting the acid chloride of the appropriate cyclohexenyl carboxylic acid in dioxane with concentrated aqueous ammonium hydroxide, with propylamine, or with a secondary amine. Alternatively, the amide may be prepared by heating the carboxylic acid in the presence or absence of a high boiling inert solvent, with ammonia or a primary or secondary amine, or by heating a carboxylic ester, in the presence or absence of an inert solvent, with ammonia or a primary or secondary amine.

EXAMPLE XXX l-Carbamyl-2-methyl-3-ethyl-4-( p-tolyl )-3- cyclohexene A mixture of 0.5 g. of 2-methyl-3-ethyl-4-(p-tolyl)4- cyclohexenecarboxylic acid and 5 ml. of thionyl chloride is refluxed for minutes and then it is evaporated and the residue is distilled to afford 0.5 g. of the acid chloride, a mobile oil of b.p. 100-110 at 0.002 mm. The distilled acid chloride is dissolved in 7 ml. of dioxane and 2 ml. of 28% aqueous ammonium hydroxide is added with stirring. The solution is then heated at 80 for 5 minutes, diluted with 100 ml. of water, and evaporated to remove most of the dioxane. The insoluble amide is extracted from the residual suspension with ether, and the ether solution is washed with dilute sodium hydroxide, dried, and evaporated. Recrystallization of the residue from aqueous methanol affords 0.4 g. of 1-carbamyl2-methyl-3-ethyl-4-(p-tolyl)-3- cyclohexene, m.p. 166-168.

Anal. Calcd. for C H ON: C, 79.33; H, 9.01

Found: C, 79.34: H, 9.10 Mmax: 2.94, 3.12, 6.06, 12.29 (KBr) NMR (CDCl 0.77, 0.88, 1.00; 1.03, 1.14; 5.97, 6.44 p m.

Following the above general procedure, and reacting the acid chloride of the appropriate cyclohexenyl acid in dioxane with concentrated aqueous ammonia, with propylamine, or with a secondary amine (25% dimethylamine in water), the following amides are prepared: 1-(N,N-Dimethylcarbamyl)-2-methyl-3-ethyl-4-(m- "anisyl)-3-cyclohexene; viscous oil of b.p. 150-155 at Anal. Calcd. for C H O N: C, 75.71; H, 9.03. Found: C, 74.02; H, 8.97. Mmax: 6.10, 7.77, 8.89, 9.50, 11.41, 12.70, 13.69, 14.21 1. NMR (CDCl;,): 0.77, 0.89, 1.01; 0.96, 1.07; 2.99, 3.13 PP 1-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(mtolyl)-4-cyclohexene; viscous oil of b.p. 135 at 0.005 mm.

Anal. Calcd. for C H ON: C, 79.95; H, 9.54.

Found: C, 79.63; H, 9.58. Mmax: 6.10, 8.80, 11.90, 12.70, 13.27, 1415a. NMR (CDCl;,): 0.81, 0.88, 0.92; 5.71 ppm. 1-(N-Propylcarbamyl)-2-methyl-3-ethyl-4-(m-tolyl)4- cyclohexene; viscous oil of b.p. 165 at 0.01 mm.

Anal. Calcd. for C H ON: C, 80.22; H, 9.76.

Found: C, 80.38; H, 10.05. Mmax: 3.02, 6.09, 11.32, 11.90, 12.74, 1418a. NMR (CDCl;,): 0.82, 0.92, 0.95, 1.06, 5.67, 6.09 ppm. In like manner there may be prepared: 1-carbamyl-2-methyl-3-ethyl-4-(p-tolyl)-4- cyclohexene, 1-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(manisyl)-4-cyclohexene, 1-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(mtolyl)-3-cyclohexene, 1-(N-propylcarbamyl)-2-methyl-3-ethyl-4-(m-tolyl)-3- cyclohexene, 1-carbamyl-2,3-dibutyl-4-(m-hydroxyphenyl)-3- cyclohexene, l-carbamyl-2-ethyl-3-propyl-4-( a-naphthyl )-4- cyclohexene, l-(N,N-dimethylcarbamyl)-2-methyl-3-ethyl-4-(o,pdiacetoxyphenyl)-4-cyclohexene, 1-carbamyl-2-methyl-3-ethyl-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexene, and l-(N-propylcarbamyl)-2-methyl-3-ethyl-4-(3,4- methylenedioxyphenyl)-4-cyclohexene.

The compounds of the present invention are active agents for the suppression of animal reproduction.

One method of determining the ability of a chemical compound to suppress reproduction is to determine its effect upon the littering of animals.

The antilittering effect of a compound is determined by administering a compound to adult rats according to the following sequence:

1. The compound to be evaluated is administered in the diet for 7 days with the sexes segregated.

2. The treatment is continued with the sexes cohabitant over a period of 15 days.

3. The sexes are segregated and observed for 21 days with no administration of the compound.

A control group is similarly treated except that no compound is administered.

Table l tabulates the minimum effective dosage of each of the compounds tested in completely suppressing littering.

TABLE I ANTILITTERING M.l .D. (per Kg.

COMPOUND TESTED hody wt/duy) Z-methyl-3-ethyl-4-(o-anisyl)-4-cyclohexenecarboxylic acid 50 g. 2-methyl-3-ethyl-4-(o-anisyl)-3-cyclohexenecarboxylic acid 250 11g. 2-methyl-3-ethyl-4-(m-anisyl)-3-cyclohexenecarboxylic acid 500 #g. 2-methy1-3;ethyl 4 (p-diethylaminoethoxyphenyl)-3-cyclohexenecarboxylic acid 2.5 mg.

TABLE I; Continued ANTILITTERING M.E.D. (per Kg. COMPOUND TESTED body wt/day) 2-methy|-3-ethy1-4-(p-diethylaminoethoxyphcnyl)-3-cyc1ohexenecarboxylic acid p-toluenesulfonate 10.0 mg. 2-methyl-3-ethy1-4-(p-thioanisy1)-3-cyc1ohexenccarboxylic acid 10.0 mg. 2-methyl-3-ethy1-4-(p-tolyl)-4-cyc1ohexenecarboxylic acid 10.0 mg. 2-methy1-3-ethy1-4-(p-tolyl)-3-cyclohexenecarboxylic acid 5.0 mg. 2-methy1-3-ethy1-4-(m-to1y1)-4cyclohexenecarboxylic acid 10 pg. 2-methyl-3-ethy1-4-(m-tolyl)-3-cyclohexenecarboxylic acid pg. 2-methy1-3-ethyl-4-(m-chlorophenyl)-4-cyclohexenecarboxylic acid 10 mg. 2-methyl3-ethy1-4-(p-dimcthylaminophenyl)-4-cyclohexenecarboxylic acid 10 mg. 2-mcthyl-3-ethyl-4-(m-hydroxyphenyl)-3-cyclohexenecarboxy1ic acid 250 pg. 2-methy1-3-ethy1-4-(o-hydroxypheny1)-3-cyc1ohexenecarboxy1ic acid 50 g. 2-methy1-3-ethyl 4-(o-methoxy-p-hydroxyphenyl)-4-cyc1ohexcnecarboxylic acid 500 pg. 2-methy1-3-ethyl-4-(o,p-diacetoxypheny1)-3-cyclohexenecarboxy1ic acid 500 g. 2-methyl-3-ethy1-4-(o,p-diacetoxyphenyl)-4-cyc1ohexenecarboxy1ic acid 100 pg. 2-methyl-3-ethyl-4'(o-hydroxy-p-acetoxyphenyl)-3-cyclohexenecarboxylic acid 200 pg. 2-methy1-3-ethy1-4-(o-hydroxy-p-acetoxyphenyl)-4-cyclohexenecarboxylic acid 100 g. 2-methyl-3-ethyl-4-(3,4-methylenedioxypheny1)-3-cyclohexenecarboxylic acid 500 pg. 2-methy1-3-ethy1-4-(3,4-mcthy1enedioxyphenyl)-4-cyc1ohexenecarboxylic acid 1000 g. 2-methyl-3-ethyl-4-(a-naphthyl) 4-cyc1ohexenecarboxylic acid 5.0 mg.

Carbinols [2-methyl-3-ethy1-4-(p-hydroxyphenyl)-3-cyclohexeny1-1lmethanol 2.5 pg. [2-methyl-3-ethy1-4-(p-hydroxyphenyl)-4-cyclohexeny1-1]methano1 5.0 g. [2-methyl-3-ethy1-4-(p-anisy1)-3-cyc1ohexeny1-1lmethanol 2.5 pg. [2-methy1-3-ethyl-4-(p-anisyl)-4-cyclohexeny1-1lmethanol 5.0 p.g (2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methano1* 10.0 pg.

Compound of Example V of US. Patent No. 3,344,147

As can be seen from the foregoing results, the substi- 25 uterus. One specific form of zygote destruction is the tuted phenyl cyclohexenyl carbinol compounds of the present invention are at least twice as active in preventing the formation of litters as the corresponding unsub stituted phenyl compounds. in addition, the compounds of the invention posses higher estrogenic activity than does the unsubstituted phenyl compound.

While the determination of the antilittering effect of a compound is important in that it shows whether or not a compound will suppress reproduction, it does not pinpoint the precise manner in which reproduction is suppressed. It has been determined that the compounds of the invention are active antizygotic agents. A zygote is the fertilized ovum, and an antizygotic agent is one which destroys the zygote prior to implantation in the lysing of the zygote.

In order to determine whether or not a compound is antizygotic, adult male and female rats are cohabited until sperm is found in the vagina. Following the presence of sperm, the female rats are dosed on two successive days with the compound, and on the ninth day after the presence of sperm is noted, the rats are autopsied and the uteri are examined for the presence of conceptuses. Lack of conceptuses indicates antizygotic effeet. A control group of rats is similarly treated except that there is no dosing with the compound under test.

Table I1 tabulates the minimum effective dosage of the compounds needed to obtain an antizygotic effect.

TABLE ll ANTIZYGOTIC M.E.D. (ug/kg Compound Tested body wt/day) 2-mcthyl-3-ethyl-4-(m-anisyl)-4-cyclohexenecarboxylic acid 1000 2-methyl-3-ethy1-4-(m-anisy1)-3-cyc1ohexenccarboxylic acid I000 2-methyl-3-ethyl-4-(o-anisyl)-4-cyclohexenecarboxy1ic acid 200 Z-mcthyl-3-ethyl-4-(o-anisyU-3-cyclohexenecarboxylic acid 500 2-methyl-3-ethyl-4-(p-diethylaminoethoxyphenyl)-3-cyc1ohexenecarboxy1ic acid p-toluenesulfonate 10,000 2-methy1-3-ethy1-4-(p-thioanisyl)-3-cyclohexenecarboxylic acid 1,000 2-methyl-3-ethyl-4-(m-tolyl)-4-cyclohexenecarboxy1ic acid 2-methyl-3-ethy1-4-(m-tolyl)-3-cyc1ohexenecarboxylic acid 50 2-methy1-3-ethyl-4-(p-ttifluoromethylpheny1)-4-cyc1ohexenecarboxylic acid 10,000 2-methyl-3-ethyl-4-(p-trifluoromethylphenyl)-3-cyc1ohexenecarboxy1ic acid 10,000 2-methyl-3-ethyl-4-(m-chlorophenyl)-4-cyclohexenccarboxy1ic acid 1,000 2 methyl-3-ethy1-4-(m-hydroxyphenyl)-3-cyclohexenecarboxylic acid 2,000 2methyl-3-ethy1-4-(o-hydroxypheny1)-3-cyclohexenecarboxylic acid 200 2methyl-3-ethy1-4-(o-methoxy-p-hydroxyphenyl)-4-cyclohexenecarboxylic acid 1,000 2-methyl-3-ethyl-4-(o,p-diacetoxyphenyl)-4-cyclohexcnecarboxylic acid 500 2-methy1-3-ethy1-4-(o-hydroxy-p-acetoxyphenyl)-4-cyclohexenecarboxy1ic acid 500 2-methyl-3-ethy1-4-(o-hydroxy-p-acetoxyphenyl)-3-cyclohexenecarboxylic acid 1,000 2-methy1-3-ethyl-4-(3,4-methylenedioxyphenyl)-4-cyclohexenecarboxy1ic acid 5.000 2-methy1-3-ethy1-4-(3,4-methy1enedioxyphenyl)-3-cyclohexenecarboxylic acid 1,000 2-methy1-3-ethyl-4-(a-naphthyl )-4-cyc1ohcxenecarboxylic acid 10.000 2-methy1-3-ethyl-4-(B-naphthyl)-4-cyclohexenecarboxylic acid 500 2-methyl-3-propy1-4-(p-anisyl)-3-cyc1ohexenecarboxy1ic acid 25 What is claimed is:

l. A compound selected from the group consisting of F R3 -\dH}cH oH and R3 QQCHEOH R1 2 1 2 4. A compound of the formula of claim 1 having the chemical name [4-(p-anisyl)-3-ethyl-2-methyl-3- cyclohexenyl-l ]methanol.

5. A compound of the formula of claim 1 having the chemical name [4-(p-anisyl)-3-ethyI-2-methyl-4- cyclohexenyl-l ]methanol.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,862,239

DATED January 21,1975

INVENTOR(S) George Karmas It rs certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Column 6,

In Column 6, line o "M59 1" should read 1 4.50 1

In Column 7, line &0, "2methyl" should read 2-methy1 In Column 7, EX.XV, A 3 should read 3- Ex.XlX A should read 4-- In Column 9, line 32, "0. 3 of should read 0. 3 g.of

In Column 10, line 10, "cyclohexenecarboxylic" should read cyclohexenecarhoxylate In Column 10, line 15, "0.99, 1.06 ppm. should read 0.99, 0.95, 1.06 ppm In Column 10, line 2%, chloride,

In Column 10, line 37,

"acid chloride." should read acid "0 7h.lo" should read c, 7h.lo

In Column 12, line 33,

line +1,

"mm (CDCL3)" should read mm (CD013) "mm (CDCL3)" should read NMR (CD013) In Column 13, delete lines 1,2, and 3.

Signed and Sealed this RUTH C. MASON Arresting Officer C. MARSHALL DANN (mnmisxrmzer nj'Parcms and Trademark-lline 35, "Example V11. should read Example V11,

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,862,239

DATED January 21,1975

INVENTOR(S) George Karmas It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Column 6, line 35, "Example vll. should read Example Vll,

In Column 6, line 1&7, "1%.59 .1'' should read lh.50 p

In Column 7, line +0, "Emethyl" should read Z-methyl In Column 7, EX.XV, 3 should read A 3- Ex.XlX A should read In Column 9, line 32, "0.3 of should read 0.3 g.o1

In Column 10, line 10, "cyclohexenecarboxylic" should read cyclohexenecarboxylate In Column 10, line 15, "0.99, l.O6 ppm. should read 0.99, 0.95, 1006 """o In Column 10, line 2 4, "acid chloride." should read acid chloride,

In Column 10, line 37, "C r.1o" should read c, 7 +.lO

In Column 12, line 33, "mm (CDCL3)" should read NMR (CD013) line rl, "NMR (CDCL3)" should read mm (cncl In Column 13, delete lines 1,2, and 3.

Signed and Scaled this nineteenth Day of August1975 [SEAL] ANCSI.

RUTH C. MASON C. MARSHALL DANN Arresring Officer (ummr'ssimrer uj'Pau'nrs and Trademarks 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF
 2. A compound of the formula of claim 1 having the chemical name (2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenyl-1)methanol.
 3. A compound of the formula of claim 1 having the chemical name (2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-1)methanol.
 4. A compound of the formula of claim 1 having the chemical name (4-(p-anisyl)-3-ethyl-2-methyl-3-cyclohexenyl-1)methanol.
 5. A compound of the formula of claim 1 having the chemical name (4-(p-anisyl)-3-ethyl-2-methyl-4-cyclohexenyl-1)methanol. 